Aqueous solution of riboflavin



Patented June 24, 1952 AQUEOUS SOLUTION OF RIBOFLAVIN Chester M.- Suter, Albany, N. Y., assignor to Sterling Drug Inc., New York, N. Y., a corporation of Delaware N Drawing. Application April 2 1951, Serial No. 223,639

, 1 This'invention relates to vitamin compositions and, specifically, to the solubilizing of riboflavin. More particularly, it relates to compositions comprising essentially riboflavin and, as a solubilizer, a non-toxic, water-soluble salt of a hydroxynaphthoic acid. Such compositions encompass those containing riboflavin as the sole dietary or therapeutic factor as well as those containing, in, addition to riboflavin, other vitamins, growth factors and medicinals.

Since riboflavin is only very sparingly soluble in water (solubility: 0.013 per cent or 0.013 g. per 100ml. of water) and other solvents suitable for pharmaceutical preparations, the use of many different agents has been proposed as solubilizing agents for this vitamin in water and in aqueous preparations. While such proposed agents may increase the solubility of riboflavin in water to some extent, the resulting solutions of many of them are not satisfactory for pharmaceutical purposes because of either toxicity or undesirable side effects after oral or parenteral administration, usually because of the large amounts of the solubilizer necessary in proportion to the amount of riboflavin solubilized. In other instances the solutions obtained are unstable and, moreover, the solubilizer itself may decompose.

. I have now found that non-toxic, water-soluble salts ofhydroxynaphthoic acids markedly increase the solubility of riboflavin in aqueous preparations. The resulting aqueous solutions, which contain considerably less solubilizer in proportion to the amount of riboflavin than in any other aqueous preparation heretofore known, are stable and suitable for oral and'parenteral administration. In addition, the preparations of my igvention, in having an outstandingly in-' creas d percentage of riboflavin compared to known riboflavin-containing aqueous preparations, offer advantages as spraying compositions for fortifying animal feeds, where a relatively high concentration of riboflavin is desired.

Sodium 3-hydroxy-2-naphthoate, because of its low cost and ready availability, is the preferred solubilizing agent according to my invention. Other solubilizing agents encompassed by my invention include other non-toxic, water-soluble salts of 3-hydroxy-2-naphthoic acid as well as non-,toxic, water-soluble salts of its isomeric hydroxynaphthoic acids,- including, l-hydroxy-Z- naphthoic acid, 4-.hydroxy-2-naphthoic acid, '7- hydroxy-Z-naphthoic acid, 2-hydroxy-1-naphthoic acid, l-hydroxy-l-naphthoic acid, 6-hydroxy-l-naphthoic acid, 8-hydroxy-l-naphthoic 4 Claims. (Crier-'81) acid, and the other isomers. Non-toxic, water-. soluble salts of these acids which can be used as solubilizers for riboflavin according to my invention include besides the sodium salts also such salts as the potassium, lithium, magnesium,- ammonium, organically-substituted ammonium salts, examples of the last-mentioned type including the 2-hydroxyethylammonium salts, the diethylammonium salts, etc., and the like. In addition to being more effective than any heretofore known compound in its solubilizing action onribofiavin in water and aqueous preparations, sodium 3-hydroxy-2-naphthoate and its related non-toxic, water-soluble salts of 3-hydroxy-Z-naphthoic acid and other hydroxynaphthoic acids also possess the advantage of providing an aqueous-solution having a pH definitely on the acid side. This is of utmost value in the formulation of aqueous preparations containing, in addition to riboflavin, other dietary factors such as vitamin B1 which is stable in the form of its salts in acid solutions and unstable in alkaline solutions.

The manufacture of my new aqueous solutions of riboflavin generallyinvolves preparing a water solution of a salt of a hydroxyn'aphthoic acid, preferably sodium 3-hydroxy 2 naphthoate. Riboflavin is then very readily dissolved in such solutions. For solutions of sodium 3-hydro'xy-2 naphthoate up to about 10 per cent, this salt was dissolved in water at room temperature. For higher percentages of this salt, up to 13.5 percent, heating was necessary. When heating was used, the resulting solution of sodium 3- hydroxy-Z-naphthoate was preferably cooled to room temperature before addition of the riboflavin and otherdietary factors. The final prod uct was then diluted with water to the desired volume.

There can be incorporated in my solubilized riboflavin preparations other water-soluble vitamins such as thiamine hydrochloride, nicotin amide, d-pantothenyl alcohol, vitamin B6 hydrochloride, vitamin C', etc., and other water soluble medicinals as, for instance, pantothenic acid, folic acid, biotin, choline chloride, inositol, etc. Also, there can be incorporated in my aqueous preparations water-insoluble vitamins, such as vitamin A, vitamin D2, vitamin D3, alpha-tocopherol, etc., and/or other water-insoluble ingredients provided, of course, a suitable solubilizing or dispersing agent is added therewith.

My invention further comprehends dry compositions comprising riboflavin and a non-toxic, water-soluble salt of a hydroxynaphthoic acid,

tions are further illustrated in the following exv amples.

Example 1 A 10.0 per cent solution of sodium 3-hydroxy- 2-naphthoate in water was found to dissolve 7.90 per cent of riboflavin. In other words, 1010 ml. of a 'water solution containing 10.0 g. of sodium B-hydroxy-Z-naphthoate dissolved 7.90 g. of'ribofiavin. The pH of this riboflavin-containing solution: was 5.90;

Similarly, 0. 5, 1.0, 2.5, and. 5.0 per cent. S0111:- tionsz ofv sodium; 3-hydroxy-2-naphthoate. dissolved, respectively; 019; :45, 1.43. and. 3.60" per cent riboflavin with the resulting solutions having pH values of 6.28, fial'l; 5.92 and 5.88, respectively; 3

Example A composition was prepared containing, .in each ml... the following ingredients:

Milligrams 'Riboflavin .5 VitaminBrhydrochloride 15 Nicotinamide 50 Vitamin. B5 hydrochloride.-- 2-.5 Galciumpantothenate. 2.5 3-hydroxy-2-naphthoatetaining" larger quantities of riboflavin can be formulated by using larger amounts of sodium 3.-hydroxy'-2=naphthoate. In addition,- the-foregoing preparation can be carried out using in place of sodium 'B -hydrOXy -Z-naphthoateother non-toxic, water-soluble salts of this acid, in-

cludingthe-potassium; lithium,- magn'esium; am-- monium, 2-hy,droxyethylammonium, diethylammonium salts; and'thelike.

' A'que'ous preparations" comparable to-the foregoing can be obtained by using as the solubilizlng; agentinon-toxic; water-soluble saltsofisomeric hydroxynaphthoic acid including sodium- 4-hydroxy 2' naphthoat'e, ammonium" 7'-hydroxy- 2-naphthoate, sodium z-hydroxy l-naphthoate, 2 4 hydroxyethylammonium 8rliydroxy-l naplithoate, and the like. I

Example 3 Forty grams of: sodium 3-hydroxy-2' naphthoate was dissolved in 306ml.- ofwater'by 'heat- I ing to boiling. The hot solution was filtered; cooled and divided-into -tw'o' portions of 150' ml; each. The pH ofthese-1l3.3 percent solutions-of sodium 3hydroxy-2*naphthoate was:6'-28. TOl-OXIB 150 m1. portion wasadded 51 ofriboflavin which dissolved-onshaking. 'I' heresulting solus- One hundred ml.

tion was diluted to 200 ml. with water. Similarly, using the other 150 ml. portion, a 200' ml. solution containing 10.5 g. of riboflavin was prepared. The pH of these two solutions was then adjusted to 6.6 by adding one drop of 1N sodium hydroxide solution. The riboflavin content of these two solutions remained constant after standing for three months at room temperature and-at 37 C.

Example 4 Anllper cent solution of sodium l-hydroxyz-naphtho'ate in water was found to dissolve 5 to 6 per cent of. riboflavin. Thus, 100 ml. or suchi.a;-.sol'ution contains 11 g. of sodium l-hydroxy-Z-naphthoate and 5 to 6 g. of riboflavin.

Example 5 The'following formulations are illustrative of polyvitamin compositions containing. in addition to riboflavin and a salt of a hydroxynaphthoic acid, other water-soluble. dietary factors as well assone; or more water-insoluble dietary factors.

Ingredient B.

Riboflavin, g 0" Sodium 3-hydroxy-2maphthoate, g. Nicotinamide; g Cholinechloride, g d-fantothenyl alcohol E Vitamin D3, g alpha-Tocopherol, g "Tween 80", g r.

Watero; s., ml

In the preparation of'tformulatioxrA the*ribo-- flavinwas dissolved in ml: of" a water'solution of the solubilizer; sodium 3=-hydroxy 2'- naphthoate. The nicotinamide, choline'chlbride and d -pantothenylalcohol were added *to' this solution and the mixture shaken until dissolution" was complete: The vitamin-D3 and alphathocopherol were then dissolved in Tween (a'water-soiub'le polyoxyethylene sorbitan monooleate); the resulting solution wasmixed ther oughly with the aforesaid'aqueous solution; water was added to bring the totalvolume up to I00 ml. and"t he resulting preparation was agitated until homogeneous;

Formulation-B-wasprepared inthe same manner as A except no alpha-tocopherol was used;

Formulations A and B were stored at room temperature and at 37C. forthree monthsand when assayed forriboflavirr content, were foundto contain the originalpotencies of this vitamin:

Other" aqueousriboflavin-containing composi tions can" be prepared-"in accordance with the foregoing" description byvarying; the number;

quantities and form ofdietary" ortherapeutic ingredientsand by adding other desirable-substances, e.- g., flavoring agents,- sweetening'agent's; etc provided they-'are-mutually compatible" with:

7 the other ingredients-- of thecomposition.

Example 6 5 Eight parts *ofsodium- 3"-hydroxy-z naphthoatewere mixed intimately. foulparts of riboflavin: This di'y preparationiwas readily solubie in one hundred part's'ofwat'er.

Similarly, other dry' compositions" cam be prepared tiiat have incorporated therein other medicinals as disclosed hereinabeve.

Alternatively, dry: compositions of my inven tionicanhe obtained by ifreeze drying my aqu'eous preparations. For example,' when? theaqueous; preparations describedi above in. Example; i or 2 were frozen: and them dehydratedfunder: vacuum while maintained ins the frozen state; there were obtained dry preparations that were readily soluble in water.

I claim:

1. An aqueous composition comprising riboflavin in a concentration higher than that ohtainable in Water alone and a non-toxic, watersoluble salt of a hydroxynaphthoic acid as a solubilizer.

2. An aqueous composition comprising riboflavin in a concentration higher than that ohtainable in water alone and a non-toxic, watersoluble, alkali metal salt of a hydroxynaphthoic acid as a solubilizer.

3. An aqueous solution comprising riboflavin in a concentration higher than that obtainable in water alone and sodium 3-hydroxy-2-naphthoate as a solubilizer.

4. A dry vitamin composition comprising riboflavin and a non-toxic, water-soluble salt of a hydroxynaphthoic acid in an amount suflicient to substantially increase the solubility of riboflavin in Water whereby the resulting aqueous solution has a concentration of riboflavin higher than that obtainable in water alone, the quantity of the hydroxynaphthoic acid salt being from about one to four times that of the riboflavin.

CHESTER M. SUTER.

REFERENCES CITED UNITED STATES PATENTS Name Date Miller Feb. 19, 1946 Number 

1. AN AQUEOUS COMPOSITION COMPRISING RIBOFLAVIN IN A CONCENTRATION HIGHER THAN THAT OBTAINABLE IN WATER ALONE AND A NON-TOXIC, WATERSOLUBLE SALT OF A HYDROXYNAPHTHOIC ACID AS A SOLUBILIZER. 